CN1083840C - 8-azabicycle [3.2.1]oct-2-ene derivs, their preparation and use - Google Patents

8-azabicycle [3.2.1]oct-2-ene derivs, their preparation and use Download PDF

Info

Publication number
CN1083840C
CN1083840C CN96197566A CN96197566A CN1083840C CN 1083840 C CN1083840 C CN 1083840C CN 96197566 A CN96197566 A CN 96197566A CN 96197566 A CN96197566 A CN 96197566A CN 1083840 C CN1083840 C CN 1083840C
Authority
CN
China
Prior art keywords
azabicyclo
oct
ene
compound
disease
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Expired - Fee Related
Application number
CN96197566A
Other languages
Chinese (zh)
Other versions
CN1199400A (en
Inventor
P·莫尔德特
J·施勒－克鲁格
G·M·奥森
E·O·尼尔森
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
NTG Nordic Transport Group AS
Original Assignee
Neurosearch AS
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Neurosearch AS filed Critical Neurosearch AS
Publication of CN1199400A publication Critical patent/CN1199400A/en
Application granted granted Critical
Publication of CN1083840C publication Critical patent/CN1083840C/en
Anticipated expiration legal-status Critical
Expired - Fee Related legal-status Critical Current

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D451/00—Heterocyclic compounds containing 8-azabicyclo [3.2.1] octane, 9-azabicyclo [3.3.1] nonane, or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane or granatane alkaloids, scopolamine; Cyclic acetals thereof
    • C07D451/02—Heterocyclic compounds containing 8-azabicyclo [3.2.1] octane, 9-azabicyclo [3.3.1] nonane, or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane or granatane alkaloids, scopolamine; Cyclic acetals thereof containing not further condensed 8-azabicyclo [3.2.1] octane or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane; Cyclic acetals thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/46—8-Azabicyclo [3.2.1] octane; Derivatives thereof, e.g. atropine, cocaine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/22—Anxiolytics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/24—Antidepressants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/04—Anorexiants; Antiobesity agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D451/00—Heterocyclic compounds containing 8-azabicyclo [3.2.1] octane, 9-azabicyclo [3.3.1] nonane, or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane or granatane alkaloids, scopolamine; Cyclic acetals thereof
    • C07D451/02—Heterocyclic compounds containing 8-azabicyclo [3.2.1] octane, 9-azabicyclo [3.3.1] nonane, or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane or granatane alkaloids, scopolamine; Cyclic acetals thereof containing not further condensed 8-azabicyclo [3.2.1] octane or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane; Cyclic acetals thereof
    • C07D451/04—Heterocyclic compounds containing 8-azabicyclo [3.2.1] octane, 9-azabicyclo [3.3.1] nonane, or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane or granatane alkaloids, scopolamine; Cyclic acetals thereof containing not further condensed 8-azabicyclo [3.2.1] octane or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane; Cyclic acetals thereof with hetero atoms directly attached in position 3 of the 8-azabicyclo [3.2.1] octane or in position 7 of the 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring system
    • C07D451/06—Oxygen atoms

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Animal Behavior & Ethology (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Medicinal Chemistry (AREA)
  • Engineering & Computer Science (AREA)
  • General Chemical & Material Sciences (AREA)
  • Neurosurgery (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Neurology (AREA)
  • Biomedical Technology (AREA)
  • Psychiatry (AREA)
  • Diabetes (AREA)
  • Pain & Pain Management (AREA)
  • Hematology (AREA)
  • Obesity (AREA)
  • Child & Adolescent Psychology (AREA)
  • Hospice & Palliative Care (AREA)
  • Emergency Medicine (AREA)
  • Epidemiology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Nitrogen Condensed Heterocyclic Rings (AREA)

Abstract

A compound having formula (I) or any of its enantiomers of any mixture thereof, or a pharmaceutically acceptable salt thereof; wherein R is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl or 2-hydroxyethyl; and R<4> is phenyl which may be substituted one or more times with substituents selected from the group consisting of halogen, CF3, CN, alkoxy, cycloalkoxy, alkyl, cycloalkyl, alkenyl, alkynyl, amino, nitro, heteroaryl and aryl; 3,4-methylenedioxyphenyl; benzyl which may be substituted one or more times with substituents selected from the group consisting of halogen, CF3, CN, alkoxy, cycloalkoxy, alkyl, cycloalkyl, alkenyl, alkynyl, amino, nitro, heteroaryl and aryl; heteroaryl which may be substituted one or more times with substituents selected from the group consisting of halogen, CF3, CN, alkoxy, cycloalkoxy, alkyl, cycloalkyl, alkenyl, alkynyl, amino, nitro, heteroaryl and aryl; or naphtyl which may be substituted one or more times with substituents selected from the group consisting of halogen, CF3, CN, alkoxy, cycloalkoxy, alkyl, cycloalkyl, alkenyl, alkynyl, amino, nitro, heteroaryl and aryl. The compounds possess valuable pharmaceutical properties as monoamine neurotransmitter re-uptake inhibitors.

Description

8-azabicyclo [3.2.1] oct-2-ene derivatives, their preparation and purposes
The present invention relates to new 8-azabicyclo (3.2.1) oct-2-ene derivatives, it is the monoamine neurotransmitter, i.e. Dopamine HCL, serotonin and NRI.Especially, the present invention relates to new 8-azabicyclo (3.2.1) oct-2-ene derivatives, it is strong serotonin reuptake inhibitor, thereby, it can be used for treating functional disorder and disease, comprise obsessional idea and behavior disease such as depressed with relevant, alarmed disease, the loss of memory, attention forfeiture superfunction disease, obesity, anxiety disorder and eating disorder.
Monoamine neurotransmitter (being Dopamine HCL, serotonin and norepinephrine) is released in the synaptic cleft, to stimulate the activity of postsynaptic receptor.The removal of monoamine neurotransmitter (or deactivation) mainly is to be undertaken by the re-uptake mechanism of presynaptic end.By suppressing re-uptake, can improve the physiologically active of monoamine neurotransmitter.
At present in anti depressant therapy, adopt norepinephrine and serotonin reuptake inhibitor as medicine (desipramine, Sensaval and former amitriptyline are NRI, and the third amidine piperazine and amitriptyline are the mixed inhibitors of serotonin reuptake transporter and norepinephrine reuptake).
People understand very few for the physiopathology of main emotion disease, it is relevant with the physiopathology of main dysthymia disorders that several neurotransmitters have been considered to.Yet, pre-clinical and clinical in the evidence of several respects all show in anti depressant therapy, the neurotransmission that improves the serotonin mediation be constitute most of recently with popular basis of adopting the pharmacological agent effect, for example fluoxetine, citalopram and paroxetine.
Self-contradictoryly be, serotonin reuptake inhibitor has suppressed the transhipment of serotonin in several minutes, and they completely antidepressant effect generally will the treatment three to around after could occur, this phenomenon shows that re-uptake inhibition itself is irrelevant with the antidepressant reaction, but further adaptations has constituted the basis of they therapeutic actions, and further adaptations has contribution to therapeutic action in other words conj.or perhaps.The antidepressant effect that this delay occurs is undoubtedly a kind of serious defective for the monoamine re-uptake inhibitor of existing employing.
Here the compound that provides is strong serotonin (5-HT) reuptake inhibitor.The compounds of this invention also has norepinephrine and dopamine reuptake suppresses active, is better than its dopamine reuptake inhibition activity but the serotonin reuptake transporter of The compounds of this invention suppresses activity.
Further, it is generally acknowledged that strong dopamine reuptake suppresses activity and often has unwanted maincenter hormesis.On the other hand, the activation to the mesolimbic dopamine system is considered to existing basis of carrying out the common mechanism of anti depressant therapy by this mechanism of raising endogenous reward system.Therefore, having dopamine reuptake that strong serotonin reuptake transporter suppresses active and have a proper equilibrium suppresses active compound a kind of reagent that antidepressant effect is occurred rapidly can be provided.
Existing demonstration, brain contains each physiological function of nervous system effect of serotonin element.It is believed that The compounds of this invention has the abilities of various and these neural system function associated imbalances in treatment Mammals, (comprising the mankind) body, eating disorder for example, depression, obsessional idea and behavior disease, alarmed disease, alcoholism, pain, the loss of memory and anxiety.Therefore The compounds of this invention provides the method for the treatment of serotonin neurotransmission reduction function associated imbalance in several and human body.These functional disorders are depressed and the function associated imbalance, as pseudodementia or Ganser ' s syndromes, migraine, voracity, obesity, corpus luteum phase syndromes after premenstrual syndrome or the menstruation, alcoholism, abuse tobacco, alarmed disease, anxiety disorder, syndromes after the wound, the loss of memory, senile dementia, social phobia, attention forfeiture superfunction disease, chronic fatigue syndrome, premature ejaculation, the difficulty of erecing, the anorexia nervosa dyssomnias, autism, disease is sent out in mutism or epilation.
Target of the present invention provides new 8-azabicyclo (3.2.1) oct-2-ene derivatives, and it is a monoamine neurotransmitter re-uptake.Especially, target of the present invention provides new strong serotonin reuptake inhibitor.
Another target of the present invention provides the pharmaceutical composition that contains new 8-azabicyclo (3.2.1) oct-2-ene derivatives, it can be used for treating active relevant with the inhibition of The compounds of this invention monoamine neurotransmitter re-uptake, particularly suppresses active function associated imbalance or disease with strong serotonin reuptake transporter.This class disease or functional disorder comprise depression and diseases associated.
It is of the present invention that to also have a target to provide treatment relevant with monoamine neurotransmitter re-uptake, particularly with the method for serotonin reuptake transporter diseases associated or functional disorder (as depression and diseases related), this method comprises one or more new 8-azabicyclo (3.2.1) oct-2-ene derivatives that gives moving animals (comprising the mankind) treatment effective dose.
For those skilled in the art, other target of the present invention will display hereinafter significantly.
The present invention especially separately or unite compound or its any enantiomorph or its any mixture or its pharmacy acceptable salt class that comprises the tool following formula Wherein
R is a hydrogen, alkyl, alkenyl, alkynyl group, cycloalkyl, cycloalkylalkyl or 2-hydroxyethyl; And
R 4Be
Phenyl, this phenyl can be selected from getting shape base one or repeatedly replacing of following groups, and substituting group is selected from: halogen, CF 3, CN, alkoxyl group, cycloalkyloxy, alkyl, cycloalkyl, alkenyl, alkynyl group, amino, nitro, heteroaryl and aryl;
3,4-methylenedioxyphenyl base;
Benzyl, this benzyl can be selected from the substituting group one of following groups or repeatedly be replaced, and substituting group is selected from: halogen, CF 3, CN, alkoxyl group, cycloalkyloxy, alkyl, cycloalkyl, alkenyl, alkynyl group, amino, nitro, heteroaryl and aryl;
Heteroaryl, this heteroaryl can be selected from the substituting group one of following groups or repeatedly be replaced, and substituting group is selected from: halogen, CF 3, CN, alkoxyl group, cycloalkyloxy, alkyl, cycloalkyl, alkenyl, alkynyl group, amino, nitro, heteroaryl and aryl; Or
Naphthyl, this naphthyl can be selected from the substituting group one of following groups or repeatedly be replaced, and substituting group is selected from: halogen, CF 3, CN, alkoxyl group, cycloalkyloxy, alkyl, cycloalkyl, alkenyl, alkynyl group, amino, nitro, heteroaryl and aryl;
Above-claimed cpd, it is (±)-3-(3, the 4-dichlorophenyl)-8-methyl-8-azabicyclo (3.2.1) oct-2-ene (±)-3-(4-chloro-phenyl-)-8-methyl-8-azabicyclo (3.2.1) oct-2-ene, or (±)-3-(3, the 4-dichlorophenyl)-8-azabicyclo (3.2.1) oct-2-ene, or its pharmaceutically acceptable addition salt class;
Pharmaceutical composition, it comprises above-claimed cpd and at least a pharmaceutically acceptable carrier or the thinner for the treatment of effective dose;
Above-claimed cpd prepares the purposes of the medicine that is used for the treatment of imbalance that life animal body (comprising the mankind) is arranged or disease, and this imbalance or disease are with to suppress monoamine neurotransmitter re-uptake in central nervous system relevant;
Above-claimed cpd prepares the purposes of the medicine that is used for the treatment of imbalance that life object (comprising the mankind) is arranged or disease, and this imbalance or disease are with to suppress the serotonin neurotransmitter re-uptake in central nervous system relevant;
Above-claimed cpd preparation is used for the treatment of the purposes of the medicine of depressed and related disorder, and above-mentioned imbalance comprises, for example pseudodementia or (anser ' s syndromes, obsessional idea and behavior disease, alarmed disease, the loss of memory, attention forfeiture superfunction disease, obesity, anxiety disorder and eating disorder;
Above-mentioned employed compound comprises: (±)-3-(3, the 4-dichlorophenyl)-8-methyl-8-azabicyclo (3.2.1) oct-2-ene (±)-3-(4-chloro-phenyl-)-8-methyl-8-azabicyclo (3.2.1) oct-2-ene, or (±)-3-(3, the 4-dichlorophenyl)-8-azabicyclo (3.2.1) oct-2-ene, or its pharmaceutically acceptable addition salt class;
Treatment has the imbalance of life animal body (comprising the mankind) or the method for disease, and above-mentioned imbalance or disease are relevant with the inhibition of monoamine neurotransmitter re-uptake, and this method comprises to these required above-claimed cpds that life treatment of animals effective dose is arranged;
Treatment has the imbalance of life animal body (comprising the mankind) or the method for disease, and above-mentioned imbalance or disease are relevant with the inhibition of serotonin reuptake transporter, and this method comprises to these required above-claimed cpds that life animal (comprising the mankind) treatment effective dose is arranged;
Aforesaid method, wherein the depression of being treated comprises with relevant imbalance, for example pseudodementia or Ganser ' s syndromes, obsessional idea and behavior disease, alarmed disease, the loss of memory, attention forfeiture superfunction disease, obesity, anxiety disorder and eating disorder; And
The preparation method of above-claimed cpd, this method comprises the dehydrating step of tool following formula: compound
Figure C9619756600091
Wherein R and R 4With above-mentioned definition, and can at random form its pharmaceutically acceptable addition salt subsequently.
The example of pharmaceutically acceptable addition salt comprises inorganic and organic acid addition salt, hydrochloride for example, hydrobromate, phosphoric acid salt, nitrate, perchlorate, vitriol, Citrate trianion, lactic acid salt, tartrate, maleate, fumarate, mandelate, benzoate, ascorbate salt, cinnamate, benzene sulfonate, mesylate, stearate, succinate, glutaminate, glycollate, tosilate, formate, malonate, naphthalene-2-sulfonic acid salt, salicylate and acetate.Known method prepares these salts in the available industry.
Other acid, for example oxalic acid itself is not pharmaceutically acceptable, can be used to prepare the salt based article as intermediate, in order to obtain compound of the present invention with and the pharmacy acceptable salt class.
Halogen is a fluorine, chlorine, bromine or iodine.
Alkyl is the alkyl of the straight or branched of 1-6 carbon atom, includes, but not limited to methyl, ethyl, propyl group, sec.-propyl, butyl, isobutyl-, the tertiary butyl, amyl group and hexyl; Preferred group is a methyl, ethyl, propyl group and sec.-propyl.
Cycloalkyl is the cycloalkyl of 3-7 carbon atom, includes, but not limited to cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.
Alkenyl is a 2-6 carbon atom, comprises at least one two key, includes, but not limited to vinyl, 1, and 2-or 2,3-propenyl, 1,2-, 2,3-or 3,4-butenyl.
Alkynyl group is a 2-6 carbon atom, comprises at least one triple bond, includes, but not limited to ethynyl, 2, and 3-proyl, 2,3-or 3,4-butynyl.
Cycloalkylalkyl is above-mentioned cycloalkyl and above-mentioned alkyl, for example cyclopropyl methyl.
Alkoxyl group is the O-alkyl, and wherein alkyl is with above-mentioned definition.
Cycloalkyloxy is the O-cycloalkyl, and wherein cycloalkyl is with above-mentioned definition.
Amino is NH 2Or NH-alkyl or N-(alkyl) 2, wherein alkyl is with above-mentioned definition.
Suitable heterocyclic aryl is 5-or 6-unit heterocycle monocyclic groups, this class heterocyclic aryl group Bao Kuo oxazole-2-Ji ， oxazole-4-Ji ， oxazole-5-base ， isoxazole-3-base isoxazole-4-base ， isoxazole-5-base, thiazol-2-yl, thiazole-4-base, thiazole-5-base, isothiazole-3-base, isothiazole-4-base, isothiazole-5-base, 1,2,4-oxadiazole-3-base, 1,2,4-oxadiazole-5-base, 1,2,4-thiadiazoles-3-base, 1,2,4-thiadiazoles-5-base, 1,2,5-oxadiazole-3-base, 1,2,5-oxadiazole-4-base, 1,2,5-thiadiazoles-3-base, 1,2,5-thiadiazoles-4-base, the 2-imidazolyl, 4-imidazolyl, 5-imidazolyl, 2-pyrryl, the 3-pyrryl, 2-furyl, 3-furyl, 2-thienyl, the 3-thienyl, the 2-pyridyl-, 3-pyridyl, 4-pyridyl.
Aryl is an aryl radical, for example phenyl or naphthyl.
I.p represents the intraperitoneal administration, and it is known administering mode.
P.o represents oral administration, and it is known administering mode.
Further, compound of the present invention can be undissolved form exist, and have water for example, ethanol or the like with pharmaceutically acceptable solvent with the dissolved form.Usually for the purpose of the present invention, the dissolved form is the same with undissolved form.
For those skilled in the art, it is obvious containing chiral centre in some compounds in the present invention, and the form of the form (that is enantiomer) that this compound can isomer exists.The present invention includes all these isomer and they mixture arbitrarily, comprise racemic compound.
Some compounds among the present invention exist with the form and the racemic form of (+) and (-).Available known method is split as optical antipode with racemic modification, and for example the diastereoisomeric salt that forms with the optics active acid separates, and then discharges optically active amine compound with alkaline purification.The another kind of method that racemic modification is split as optical antipode is based on the method for the chromatography of optically active matrix.Thereby racemic compound of the present invention can be split as its optically active enantiomorph, for example adopts the method for fractional crystallization d-or 1-(tartrate, amygdalic acid or camphorsulfonic acid) salt.The form that compound of the present invention also can form diastereomeric acid amides splits, be about to compound of the present invention and optically active carboxylic acid reacts, for example from (+) or (-) phenylalanine, (+) or (-) phenylglycine, (+) or (-) dextrocamphoric acid, or compound of the present invention and optically active chloro-formic ester or analogue reacted, generate diastereomeric carbamate.
Also can adopt other the method that those skilled in the art knew and used to split optical isomer.These methods are seen J.Jaques, A.collet and S.wilen " Enantiomers, Racemates, and Resolutions " John Wiley and Sons is described in the New York (1981).
Can in all sorts of ways and prepare compound of the present invention.Thereby, can prepare compound of the present invention and pharmaceutically acceptable derivates thereof with the known method for preparing the similar structures compound, and illustrate with following representative instance respectively.
Following route has illustrated a kind of method for preparing The compounds of this invention:
Figure C9619756600121
Substituent R in reaction scheme and R 4With above-mentioned definition, and X is Li, MgBr or arbitrarily other type be suitable for generating the functional group of carbanion as its counterpart.
Can adopt conventional mode to realize method in the above-mentioned reaction scheme.The dehydration of alcohol adopts acid to carry out, for example with hydrochloric acid or sulfuric acid or other conventional dewatering agent, for example P 2O 5Or SOCl 2
Can adopt conventional method that compound of the present invention is converted into another compound of the present invention.
Employed initiator is known in the method for the invention, or available known method prepares from the material that can buy.
Product in the described reaction can for example extract through the mode of routine, crystallization, and distillation, chromatography waits and separates.
Biology
The compounds of this invention is measured the ability that the Dopamine HCL in synaptosome (DA), norepinephrine (NA) and serotonin (5-HT) picked-up suppress.Background: can suppose by from synaptic cleft, removing neurotransmitter dopamine, norepinephrine and serotonin, can play the effect that stops corresponding nerve signal at the neurotransmitter transhipment/re-uptake position of nerve ending.The activity of transhipment whole protein can be right by cynapse 3The H-Dopamine HCL, 3The H-norepinephrine and 3The experiment in vitro of H-5-hydroxy-tryptamine re-uptake is correspondingly measured.
Right in the striatum cynapse 3The H-Dopamine HCL ( 3H-DA) She Qu vitro inhibition tissue preparation: except as otherwise noted, preparation is carried out under 0-4 ℃.Use the Ultra-Turrax homogenizer, in containing the ice-cold 0.32M sucrose of 1mM Pargyline, 100 times of volumes, to taking from putting shape body (150-200g) homogenate 5-10 second of male Wistar rat.In the presence of Pargyline, the activity of monoamine oxidase will be suppressed.Homogenate under 1000 * g centrifugal 10 minutes.The supernatant liquor that generates under 27,000 * g centrifugal 50 minutes again, abandoning supernatant then.With small-particle (P 2) resuspending is in containing 122mM NaCl, 0.16mM EDTA, 4.8mM KCl, 12.7mM Na 2HPO 4, 3.0mM NaH 2PO 4, 1.2mM MgSO 4, 1mMCaCl 2, 10mM glucose and 1mM xitix are also oxidized (at 96%O 2: 4%CO 2Following balance at least 30 minutes) Krebs-Ringer cultivates in the damping fluid (pH=7.2, every g fundamental weave consumption 8000ml).Measure: the aliquots containig of 4.0ml suspensions of tissues is added to 100 μ l is tried solution and 100 μ l 3Among the H-DA (1nM, ultimate density), mixture was cultivated 25 minutes down in 37 ℃.Carrying out non-specific re-uptake with Benzatropine (10 μ M, ultimate density) measures.After the sample cultivation, under the suction filtration condition directly in the impouring Whatman GF/C glass fibre funnel, funnel is with ice-cold 0.9% (w/v) NaCl solution washing of 5ml 3 times.Liquid scintillation number scale with routine is measured the radioactivity amount of substance on the funnel.Specific re-uptake can calculate by the difference between total picked-up and the nonspecific picked-up.
Calculating IC 50Before the value, need obtain 25-75% specificity bonded inhibiting rate.
Measured value is with IC 50(work as inhibition 3The H-DA specificity is in conjunction with reaching at 50% o'clock, the concentration of test-compound (μ M)) form of value provides.
Right in the hippocampus cynapse 3The H-norepinephrine ( 3H-NA) She Qu vitro inhibition tissue preparation: except as otherwise noted, preparation is carried out under 0-4 ℃.Use the Ultra-Turrax homogenizer, in containing the ice-cold 0.32M sucrose of 1mM Pargyline, 100 times of volumes, to hippocampus (150-200g) the homogenate 5-10 second of taking from male Wistar rat.In the presence of Pargyline, the activity of monoamine oxidase will be suppressed.Homogenate under 1000 * g centrifugal 10 minutes.The supernatant liquor that generates under 27,000 * g centrifugal 50 minutes again, abandoning supernatant then.With small-particle (P 2) resuspending is in containing 122mM NaCl, 0.16mM EDTA, 4.8mM KCl, 12.7mM Na 2HPO 4, 3.0mM NaH 2PO 4, 1.2mM MgSO 4, 0.97mMCaCl 2, 10mM glucose and 1mM xitix are also oxidized (at 96%O 2: 4%CO 2Following balance at least 30 minutes) Krebs-Ringer cultivates in the damping fluid (pH=7.2, every g fundamental weave consumption 2000ml).Measure: the aliquots containig of 4.0ml suspensions of tissues is added to 100 μ l is tried solution and 100 μ l 3Among the H-NA (1nM, ultimate density), mixture was cultivated 90 minutes down in 37 ℃.Carrying out non-specific re-uptake with Desipramine (1 μ M, ultimate density) measures.After the sample cultivation, under the suction filtration condition directly in the impouring Whatman GF/C glass fibre funnel, funnel is with ice-cold 0.9% (w/v) NaCl solution washing of 5ml 3 times.Liquid scintillation number scale with routine is measured the radioactivity amount of substance on the funnel.Specific re-uptake can calculate by the difference between total picked-up and the nonspecific picked-up.
Calculating IC 50Before the value, need obtain 25-75% specificity bonded inhibiting rate.
Measured value is with IC 50(work as inhibition 3The H-NA specificity is in conjunction with reaching at 50% o'clock, the concentration of test-compound (μ M)) form of value provides.
In the cortex cynapse 3The H-5-hydroxy-tryptamine ( 3H-5-HT) She Qu vitro inhibition tissue preparation: except as otherwise noted, preparation is carried out under 0-4 ℃.Use the Ultra-Turrax homogenizer, in containing the ice-cold 0.32M sucrose of 1mM Pargyline, 100 times of volumes, to pallium (150-200g) the homogenate 5-10 second of taking from male Wistar rat.In the presence of Pargyline, the activity of monoamine oxidase will be suppressed.Homogenate under 1000 * g centrifugal 10 minutes.The supernatant liquor that generates under 27,000 * g centrifugal 50 minutes again, abandoning supernatant then.With small-particle (P 2) resuspending is in containing 122mM NaCl, 0.16nM EDTA, 4.8mM KCl, 12.7mM Na 2HPO 4, 3.0mM NaH 2PO 4, 1.2mM MgSO 4, 1mMCaCl 2, 10mM glucose and 1mM xitix are also oxidized (at 96%O 2: balance is at least 30 minutes under the 4%CO2) Krebs-Ringer cultivates in the damping fluid (pH=7.2, every g fundamental weave consumption 1000ml).Measure: the aliquots containig of 4.0ml suspensions of tissues is added to 100 μ l is tried solution and 100 μ l 3Among the H-5-HT (1nM, ultimate density), mixture was cultivated 30 minutes down in 37 ℃.Carrying out non-specific re-uptake with citalopram (1 μ M, ultimate density) measures.After the sample cultivation, under the suction filtration condition directly in the impouring Whatman GF/C glass fibre funnel, funnel is with ice-cold 0.9% (w/v) NaCl solution washing of 5ml 3 times.Liquid scintillation number scale with routine is measured the radioactivity amount of substance on the funnel.Specific re-uptake can calculate by the difference between total picked-up and the nonspecific picked-up.
Calculating IC 50Before the value, need obtain 25-75% specificity bonded inhibiting rate.
Measured value is with IC 50(work as inhibition 3The H-5-HT specificity is in conjunction with reaching at 50% o'clock, the concentration of test-compound (μ M)) form of value provides.
To the results are shown in the following table of measuring through the The compounds of this invention of selecting:
Table 2
Test-compound 5-HT-re-uptake DA-picked-up NA-picked-up
IC 50(μ M) IC 50(μ M) IC 50(μ M) (±)-3-(3, the 4-dichlorophenyl)-8-methyl-8-azepine 0.079 0.026 0.0047 dicyclo (3.2.1) oct-2-ene
Above-mentioned experiment in vitro result shows that this compound is the reuptake inhibitor of monoamine neurotransmitter, particularly serotonin.
In addition, also the antidepressant activity of The compounds of this invention is measured.
Outstanding tail experiment background: after system gives maincenter stimulant and antidepressive, can observe the set time of the mouse that is suspended that is suspended to afterbody and reduce (Steru, L., Chermat, R., Thierry, B.﹠amp; Simon, P. (1985) The tail suspension test:A new method for screeningantidepressants in mice.Psychophamacology 85:367-370).Method:
Make female NMRI mouse (20-25g) in a room, be familiar with 16 hours at least (12 hours bright/black), put 25 mouse in every cage., be suspended on the bar at 30cm place, lab platform top after 30 minutes at orally give carrier or medicine with the afterbody of viscous adhesive with mouse.In ensuing 6 minutes, the record cumulative set time, being decided to be health or brothers does not have motion (head movement is not considered as motion).Each dosage experimentizes with 6 mouse.
The set time average out to 160-180 second of the mouse that crosses with salt solution or vehicle treated.ED 50Value can be calculated by the figure marker method that at least 3 dosage (reduce to when the set time 100 seconds dosage) obtain.
The ED of compound (±)-3-(3, the 4-dichlorophenyl)-8-methyl-8-azabicyclo (3.2.1) oct-2-ene 50Value is 0.96mg/kg.
Result shown in above-mentioned has indicated that The compounds of this invention has strong antidepressant activity.
Pharmaceutical composition
When can be applicable to treat, The compounds of this invention can be taken by the mode of former chemical, but preferably provides activeconstituents with the form of pharmaceutical composition.
Thereby, the invention further relates to pharmaceutical composition, said composition contains compound of the present invention or its pharmacy acceptable salt or derivative and one or more pharmaceutically acceptable carrier, and at random other treats and/or prevents composition.This carrier must be " acceptable " on compatibility with other composition, and is harmless to curer.
Pharmaceutical composition comprises that those are suitable for the formulation of oral, rectum, nasal cavity, part (comprising oral cavity and hypogloeeis), vagina or non-enteron aisle (comprising intramuscular, subcutaneous and vein) administration, or is suitable for sucking or being blown into the formulation of administration.
Therefore, The compounds of this invention can be prepared into pharmaceutical compositions and unit dosage form thereof with adjuvant, carrier or the thinner of routine, but this formulation solid, for example tablet or filled capsules, or liquid, for example solution, suspension agent, emulsion, elixir or its capsule of filling, they are and orally use, and this formulation also is used for the suppository that rectum uses; Or be used for (comprising subcutaneous) aseptic injection that non-enteron aisle uses.These pharmaceutical compositions and unit dosage thereof can contain the conventional ingredient of conventional content, have or do not have additional active compound or composition, and with respect to the every day that will use for the dosage range, this unit dosage can contain any appropriate effective amount of actives.According to the suitable unit dosage of representative, fill a prescription every and contain 10 milligrams of activeconstituentss, or more widely every contain 0.1-100 milligram activeconstituents.
The compounds of this invention can the administration of oral widely or non-enteron aisle mode.Following dosage forms can contain as the compound of the present invention of activeconstituents or its pharmacy acceptable salt, and this fact is conspicuous for those skilled in the art.
For from the The compounds of this invention pharmaceutical compositions, used pharmaceutically acceptable carrier can be solid or liquid.Solid preparation comprises pulvis, tablet, pill, capsule, cachet, suppository and dispersible granule.Solid carrier can be one or more material, and they can be thinner, seasonings, stablizer, lubricant, suspension agent, tackiness agent, sanitas, tablet disintegrant or become capsule material.
In pulvis, carrier is the pressed powder of porphyrize, and the activeconstituents of it and porphyrize is mixed together.
In tablet, activeconstituents be with the carrier with certain bounding force by suitable mixed, and be pressed into required shape and size.
Pulvis and tablet preferably contain 5 or the active compound of 10%-70%.Solid carrier be magnesiumcarbonate, Magnesium Stearate, talcum, sugar, lactose, pectin, dextrin, starch, gelatin, tragacanth gum, methylcellulose gum, Xylo-Mucine, low-melting wax, theobroma oil, or the like.Terms " formulation " comprises active compound and the prescription that becomes capsule material to form as carrier, and wherein the active ingredient suppressed by vector with or without carrier encases.Equally also comprise cachet and lozenge.Tablet, pulvis, capsule, pill, cachet and lozenge are adoptable suitable oral dosage forms.
For preparation bolt system, at first, under agitation activeconstituents is dispersed in wherein then low-melting wax (for example fatty acid glycerine fat or theobroma oil) fusing.In the conventional big or small mould of the uniform mixture impouring of this fusing, make it cooling, solidify then.
The suitable prescription that is used for vagina administration can provide with the form of medicated vaginal suppository, tampon, creme, paste, foaming agent or sprays.Except activeconstituents, also has the suitable carrier of knowing in this area in the above-mentioned preparation.
This preparation of liquid comprises solution, suspension and emulsion, and for example water or water-propylene glycol solution, non-enteron aisle injecting fluid preparation can be mixed with the solution form of hydration polyoxyethylene glycol.
Therefore, the preparation that The compounds of this invention can be mixed with parenterai administration (for example, injection, for example large bolus injection or persistence transfusion) or can the ampoule form, the unitary dose of prepackage syringe form, multi-dose container primary infusion or that have sanitas provides.Composition can adopt suspension agent, the emulsion form of solution or oiliness or aqueous carrier, and can contain prescription and use reagent, suspension agent for example, stablizer with or dispersion agent.In addition, activeconstituents can powder type exists, and it can obtain by sterile solid being carried out aseptic separation or carry out lyophilize by solution, before use, use suitable carriers, for example utilizes asepticly, and apyrogenic water is prepared.
The aqueous solution that is fit to orally use can follow these steps to prepare, and is about to activeconstituents and is dissolved in the water, and can add suitable tinting material, flavouring agent, stablizer and viscosifying agent as required.
The aqeous suspension that is fit to orally use can follow these steps to prepare, and is about to grind levigated activeconstituents and dope and is dispersed in the water, for example natural or synthetic glue, resin, methylcellulose gum, Xylo-Mucine or other known suspension agent.
Also comprise solid preparation in addition, before closing on use, be translated into that these liquid preparations comprise solution, suspension agent and emulsion for oral liquid preparation.Except activeconstituents, these preparations also can contain tinting material, seasonings, stablizer, buffer reagent, artificial or natural sweeting agent, dispersion agent, viscosifying agent, solubility promoter or the like.
The The compounds of this invention that is used for topical can be mixed with ointment, creme or washing lotion, or with the transdermal route administration.Ointment and creme can water or oleaginous base prepare, and can have suitable viscosifying agent and/or gelifying agent.Washing lotion can water or oleaginous base prepare, and contain one or more emulsifying agent, stablizer, dispersion agent, suspension agent, viscosifying agent or tinting material usually.
The prescription that is fit to local oral administration comprises the lozenge that contains activeconstituents, and above-mentioned activeconstituents is present in the flavoured base, is generally sucrose and gum arabic or tragacanth gum; The lozenge that comprises activeconstituents, this activeconstituents is present in the inert base, in gelatin and glycerine or sucrose and gum arabic; And the collutory that comprises activeconstituents, this activeconstituents is present in the suitable liquid vehicle.
Solution or suspension (for example dropper, suction pipe or spray method) according to a conventional method are directly used in nasal cavity.This prescription can be single or the multiple doses form provide.When adopting dropper or suction pipe method, can control the solution or the suspension of the suitable volumes of being scheduled to by patient oneself.Under the spraying situation, can come administration by the atomisation pump of metering.
Respiratory tract administration can adopt aerosol preparations, wherein contains the activeconstituents of pressurized packing, and has suitable propelling agent, as chlorofluorocarbon (CFC), Refrigerant 12 for example, trichlorofluoromethane or dichloro tetrafluoro ethane, carbonic acid gas or other suitable gas.Aerosol can contain tensio-active agent easily, as Yelkin TTS.The dosage of medicine can be controlled by the metering valve that provides.
In addition, the form that activeconstituents can dry powder provides, for example the powdered mixture of compound and suitable powder matrix.Above-mentioned powder matrix machine comprises lactose, starch, starch derivative, as Vltra tears and polyvinylpyrrolidone (PVP).Easily, powder carrier will form gel at nasal cavity.Powder composition can unit dosage form exists, and as capsule or gelatin tube, or exists with the blister-pack form, and powder wherein can pass through inhalation.
The prescription that is used for respiratory tract administration comprises prescription in the nose, and compound wherein generally has smaller particle size, for example 5 microns or littler.Such particle diameter can obtain with the method for knowing in this field, for example by reducing the method for particle volume.
When needs, can adopt the slowly-releasing prescription form of activeconstituents.
Pharmaceutical preparation preferably exists with unit dosage form.In this form, preparation is divided into the unitary dose that contains an amount of activeconstituents.Above-mentioned unit dosage form can be the preparation of a packing, and this packing contains the preparation of independent packing, for example Bao Zhuan tablet, capsule and be present in bottle or ampoule in powder.In addition, unit dosage form also can be capsule, tablet, cachet or a lozenge itself, or it can be a preparation any suitable quantity and that exist with above-mentioned packaged form.
The tablet or the capsule that are used for oral administration are comparatively desirable preparations with the liquid that is used for intravenously administrable.
Methods of treatment
Because The compounds of this invention has serotonin and dopamine uptake suppresses active and lower side effect, so it is exceedingly useful aspect treatment depression and diseases related.These character make The compounds of this invention exceedingly useful aspect the depressed and relevant imbalance of treatment, above-mentioned imbalance comprises obsessional idea and behavior disease, alarmed disease, the loss of memory, attention forfeiture superfunction disease, obesity, anxiety disorder and eating disorder, and to the serotonin of The compounds of this invention and other imbalance of the active sensitivity of dopamine reuptake inhibition.Therefore what can give required treatment has life animal body (comprising a mankind) The compounds of this invention, suppresses the relevant symptom of activity with alleviation or elimination with serotonin and dopamine reuptake.These diseases are particularly including Parkinson's disease, dysthymia disorders, obesity, narcolepsy and Drug abuse.
Suitable dosage range every day is the 0.1-500 mg/day, 10-70 mg/day particularly, every day, administration was 1-2 time, this depends primarily on the object and the body weight thereof of the formulation of administering mode, administration accurately, the disease of being treated, treatment, depends on doctor in charge or animal doctor's personal choice and experience further.
Following example will further specify the present invention, but not limit the present invention.
Example 13-(3, the 4-dichlorophenyl)-8-methyl-8-azabicyclo (3.2.1) suffering-3-alcohol
With the 1-bromo-3 that stirs, (178.6g, ether 0.8mol) (1430ml) solution is cooled to-70 ℃ to the 4-dichlorobenzene under argon gas.Hexane (the 310mL 2.5M that slowly adds n-Butyl Lithium; 0.78mol) solution, and keep temperature to be lower than-65 ℃ (joining day is 1 hour).The solution of gained adds 8-methyl-8-azabicyclo (3.2.1) suffering-3-ketone (50g, anhydrous tetrahydro furan 0.36mol) (360ml) solution subsequently-70 ℃ of following restir 30 minutes.Keep temperature to be lower than-50 ℃ in adition process, the joining day is approximately 1 hour.The solution of gained added entry (215mL) again-50 ℃ of following restir 2 hours in 15 minutes, and added 4M HCl (360nL) in 25 minutes.The temperature that adds the end is-20 ℃.Tell organic phase, water with ether (500mL) washing once.Add dense NH to aqueous phase 4OH (approximately 200mL) is to pH=10, and it causes the title compound precipitation.The thick product of filtering separation, and water (2 * 300mL) suspension secondaries, finally dry under lamp, get white solid title compound (88g, 86%), m.p.179.3-180.5 ℃.
Following compounds can prepare with similar methods: 3-(4-chloro-phenyl-)-8-methyl-8-azabicyclo (3.2.1) suffering-3-alcohol:
From 4-bromine chlorinated benzene (15.4g, 81mmol), the hexane solution of n-Butyl Lithium (31mL, 2.5M; 78mmol) with the 8-methyl-(5g 36mmol) prepares title compound to 8-azabicyclo (3.2.1) suffering-3-ketone.Get 5.7g (63%) white solid, m.p.186.3-187 ℃.8-methyl-3-phenyl-8-azabicyclo (3.2.1) suffering-3-alcohol:
From bromobenzene (42.1mL, 0.4mol), the hexane solution of n-Butyl Lithium (156mL, 2.5M; 0.39mmol) and the 8-methyl-(25g 0.18mol) prepares title compound to 8-azabicyclo (3.2.1) suffering-3-ketone.Get 14g (36%) product, m.p.157-159 ℃.8-methyl-3-(4-aminomethyl phenyl)-8-azabicyclo (3.2.1) suffering-3-alcohol:
From the 4-toluene bromide (13.9g, 81.4mmol), the hexane solution of n-Butyl Lithium (31.2mL 2.5M; 78mmol) with the 8-methyl-(5g, 35.9mmol) (40mL) prepares title compound to 8-azabicyclo (3.2.1) suffering-3-ketone in anhydrous tetrahydro furan.Get 3.5g (42%) white solid, m.p.247-249 ℃.3-(4-methoxyphenyl)-8-methyl-8-azabicyclo (3.2.1) suffering-3-alcohol:
From the 4-bromoanisole (15.1g, 80.5mmol), the hexane solution of n-Butyl Lithium (31.2mL 2.5M; 77.9mmol) and the 8-methyl-(5g, 36mmol) (40mL) prepares title compound to 8-azabicyclo (3.2.1) suffering-3-ketone in anhydrous tetrahydro furan.Get 2.1g (24%) product, m.p.161.8-162.3 ℃.8-methyl-3-(4-trifluoromethyl)-8-azabicyclo (3.2.1) suffering-3-alcohol:
From the 4-5 bromine benzotrifluoride, the hexane solution of n-Butyl Lithium (31.2mL 2.5M; 77.9mmol) and the 8-methyl-(5g 36mmol) prepares title compound to 8-azabicyclo (3.2.1) suffering-3-ketone.Get 6.2g (60%) yellow solid, m.p.189.2-190.5 ℃.3-(4-fluorophenyl)-8-methyl-8-azabicyclo (3.2.1) suffering-3-alcohol:
From the 4-bromofluoro benzene (26.3g, 0.15mol), the hexane solution of n-Butyl Lithium (60mL 2.5M; 0.15mol) and the 8-methyl-(10g 71.7mmol) prepares title compound to 8-azabicyclo (3.2.1) suffering-3-ketone.Get 9.9g (59%) product, m.p.168.5-170 ℃.
Example 2 (±)-3-(3,4-dichloro-phenyl)-8-methyl-8-azabicyclo (3.2.1) oct-2-ene:
Under the room temperature, (50g adds concentrated hydrochloric acid (50mL) in glacial acetic acid 0.17mol) (160ml) solution to the 3-that is stirring (3,4-dichloro-phenyl)-8-methyl-8-azabicyclo (3.2.1) suffering-3-alcohol.Mixture heating up refluxes.After 20 minutes, initiator is exhausted, in the about 1.5L trash ice of mixture impouring.In the aqueous solution that generates, add dense NH 4OH (approximately 325mL) is to pH=9-10, and it causes gluing solid precipitation.Decantation mixture, resistates are developed in water (1.5L), get the thick product of crystallinity.The thick last water of product (300mL) washing, the stink cupboard inner drying gets beige solid shape title compound, m.p.44-52 ℃.
Following compounds can prepare with similar methods: (±)-3-(4-chlorophenyl)-8-methyl-8-azabicyclo (3.2.1) oct-2-ene malonic ester:
From-(4g, 16mmol), glacial acetic acid (15ml) and concentrated hydrochloric acid (15ml) prepare title compound to 3-(4-chlorophenyl)-8-methyl-8-azabicyclo (3.2.1) suffering-3-alcohol.The productive rate of free alkali is (3.6g, 97%).(1.44g 6mmol) is dissolved in (96%) in the ethanol, adds propanedioic acid (0.62g, ethanol 6mmol) (96%) solution with the part free alkali.Solution concentration to one oily matter that generates is developed in ether, and title compound precipitates with powder type, filtering separation.Productive rate is (1.4g, 71%), and it is a white crystals, m.p.100.8-102.1 ℃.(±)-8-methyl-3-phenyl-8-azabicyclo (3.2.1) oct-2-ene malonic ester:
From-(8g, 37mmol), glacial acetic acid (25ml) and concentrated hydrochloric acid (8ml) prepare title compound to 8-methyl-3-phenyl-8-azabicyclo (3.2.1) suffering-3-alcohol.(7.4g 37mmol) is dissolved in (20ml) in the dehydrated alcohol, adds propanedioic acid (3.9g with the title compound free alkali, 37.5mmol), the vlil several minutes is when solution is still warm, remove by filter some impurity, cooling, 5 ℃ keep a little while down, put into crystal seed then, title compound begins precipitation, 5 ℃ kept down after two hours, the filtering separation title compound, and crystallization is with cold absolute ethanol washing (10ml).Output 5.9g (53%), m.p.131-131.8 ℃.(±)-8-methyl-3-(4-aminomethyl phenyl)-8-azabicyclo (3.2.1) oct-2-ene fumarate:
From 8-methyl-3-(4-aminomethyl phenyl)-8-azabicyclo (3.2.1) suffering-3-alcohol (3.4g14.7mmol), glacial acetic acid (11ml) and concentrated hydrochloric acid (11ml) prepare title compound.The free alkali of title compound is dissolved in the ether, and adds fumaric acid (1.3g, methanol solution 11.2mmol).The solution concentration that generates is to doing, and residue is developed in ether, and title compound precipitates with powder type, filtering separation.Output is 2.46g (51%), m.p.156.8-157.4 ℃.(±)-3-(4-p-methoxy-phenyl)-8-methyl-8-azabicyclo (3.2.1) oct-2-ene fumarate:
From 3-(4-p-methoxy-phenyl)-8-methyl-8-azabicyclo (3.2.1) suffering-3-alcohol (2g8mmol), glacial acetic acid (6.4ml) and concentrated hydrochloric acid (6.4ml) prepare title compound.The free alkali of title compound is dissolved in the ethanol (96%), and (0.8g, 6.9mmol), precipitation occurs, and the solution concentration that generates is extremely done residue dehydrated alcohol recrystallization to add fumaric acid.Output is 1.1g (40%), white crystals, 8.7 ℃ of m.p.167.3-16.(±)-8-methyl-3-(4-trifluoromethyl)-8-azabicyclo (3.2.1) oct-2-ene malonic ester:
From 8-methyl-3-(4-trifluoromethyl)-8-azabicyclo (3.2.1) suffering-3-alcohol (5g17.5mmol), glacial acetic acid (16ml) and concentrated hydrochloric acid (16ml) prepare title compound.The free alkali of title compound is dissolved in the ethanol (96%), and (1.17g, 11.2mmol) 96% ethanolic soln are extremely done the solution concentration that generates, and residue is developed in ether, and title compound precipitates with powder type, filtering separation to add propanedioic acid.Output is 3.9g (60%), m.p.106.7-107.8 ℃.(±)-3-(4-fluorophenyl)-8-methyl-8-azabicyclo (3.2.1) oct-2-ene malonic ester:
From 3-(4-fluorophenyl)-8-methyl-8-azabicyclo (3.2.1) suffering-3-alcohol (4.7g20mmol), glacial acetic acid (20ml) and concentrated hydrochloric acid (20ml) prepare title compound.The free alkali of title compound is dissolved in the Virahol, and (1.7g, 16.3mmol), after a while, title compound precipitates with powder type, filtering separation to add propanedioic acid.Output is 4.6g (72%), m.p.122.2-123 ℃.
Example 3 (±)-3-(4-chloro-phenyl-)-8-azabicyclo (3.2.1) oct-2-ene malonic ester:
Anhydrous 1 toward 3-(4-chloro-phenyl-)-8-methyl-8-azabicyclo (3.2.1) oct-2-ene (2g8.5mmol) that stirs, in 2-ethylene dichloride (20ml) solution, under the nitrogen, add chloroformic acid 1-chloro-ethyl ester (1,25ml, 11.6mmol).The reaction mixture reflux is spent the night, and (1ml 9.3mmol), spends the night the reaction mixture reflux once more to add 1-chloroethyl chloro-formic ester then.Compound of reaction is concentrated into oily, this oil is dissolved in the methyl alcohol (25ml), vlil 2 hours is concentrated into oily then, and residue is soluble in water, and adds strong aqua to pH=10, the water ether extraction.Organic phase is with dried over mgso and be concentrated into dried.Residue is through silica gel column chromatography (methylene dichloride/acetone/methanol=4/1/1 (v/v)).The product cut is concentrated into oily, this oil is dissolved in the ethanol (95%), and the adding propanedioic acid (0.55g, 5.3mmol) ethanol (95%) solution is concentrated into oily with it, and with the ether development, title compound precipitates with powder type, filtering separation.Output is 1.32g (48%), m.p.136.1-138 ℃.Following compounds can prepare with similar methods: (±)-3-(4-fluorophenyl)-8-azabicyclo (3.2.1) oct-2-ene malonic ester:
(1.6g, 7.37mmol) (1.2mL, 1.6g 11mmol) prepare title compound with chloroformic acid 1-chloro-ethyl ester from (±)-3-(4-fluorophenyl)-8-methyl-8-azabicyclo (3.2.1) oct-2-ene.The free alkali of title compound is dissolved in Virahol and adds propanedioic acid (0.43g, 4.1mmol), title compound precipitates with powder type, filtering separation.Productive rate is 1.14g (50%), m.p.132.2-132.6 ℃.
Example 4 (±)-3-(3, the 4-dichlorophenyl)-8-azabicyclo (3.2.1) oct-2-ene malonic ester:
Anhydrous 1 toward (±)-3-(3, the 4-dichlorophenyl)-8-methyl-8-azabicyclo (3.2.1) oct-2-ene (10g 37mmol) that stirs in 2-ethylene dichloride (100ml) solution, under the nitrogen, adds chloroformic acid 1-chloro-ethyl ester (8ml, 10.6g 74mmol).The reaction mixture reflux is spent the night, add then chloroformic acid 1-chloro-ethyl ester (4ml, 5.3g, 37mmol), once more with reaction mixture reflux 4 hours.Compound of reaction is concentrated into dried, should residually mix and be dissolved in the methyl alcohol, vlil 2 hours, be concentrated into dried then, residue is through silica gel column chromatography (use methylene dichloride/acetone/methanol=4/1/1 (v/v) wash-out then with methylene chloride=9/1 (v/v) wash-out, use methanol-eluted fractions at last).Be concentrated into the product cut dried, with this resistates (1.8g, other is an initial compounds) be dissolved in the Glacial acetic acid (10mL), add entry (5nL) and zinc powder (1g 15.2mmol), reaction mixture at room temperature stirs and spends the night, it to water, and is added strong aqua to pH=10, the water ether extraction.Organic phase washes and uses dried over mgso with water, is concentrated into oily.This oil is at room temperature placed crystallization.Solid is dissolved in the ethanol (95%), adds 4M sodium hydroxide (5nL) solution, and the reaction mixture reflux is spent the night.Add 4M sodium hydroxide (10mL) solution again, and the reaction mixture reflux is spent the night.And then add 4M sodium hydroxide (10mL) solution, and made the reaction mixture reflux 4 hours.Concentrated reaction mixture does not exist to there being ethanol, adds entry in concentration process, to keep the liquor capacity constant.Gained solution ether extraction, organic phase is with dried over mgso and be concentrated into brown oily resistates, through silica gel (50g) chromatography (methylene dichloride/acetone/methanol=4/1/1 (v/v)).The product cut is concentrated into oily, this oil is dissolved in the ethanol (95%), (0.3g 0.29mmol), is settled out title compound, filtering separation from this solution to add propanedioic acid.Output is 1.32g (48%), m.p.136.1-138 ℃.Be concentrated into oily, with the ether development, title compound precipitates with powder type, filtering separation.Output is 0.65g (5.5%), m.p.110-112 ℃.

Claims (8)

1. have compound or its any enantiomorph or its any mixture of following formula or its pharmacy acceptable salt class; Wherein
R is a hydrogen, alkyl, alkenyl, alkynyl group, cycloalkyl, cycloalkylalkyl or 2-hydroxyethyl; And
R 4Be
Phenyl, this phenyl can be selected from the substituting group one of following groups or repeatedly be replaced, and substituting group is selected from: halogen, CF 3, CN, alkoxyl group, cycloalkyloxy, alkyl, cycloalkyl, alkenyl, alkynyl group, amino, nitro, heteroaryl and aryl;
3,4-methylenedioxyphenyl base;
Benzyl, this benzyl can be selected from the substituting group one of following groups or repeatedly be replaced, and substituting group is selected from: halogen, CF 3, CN, alkoxyl group, cycloalkyloxy, alkyl, cycloalkyl, alkenyl, alkynyl group, amino, nitro, heteroaryl and aryl;
Heteroaryl, this heteroaryl can be selected from the substituting group one of following groups or repeatedly be replaced, and substituting group is selected from: halogen, CF 3, CN, alkoxyl group, cycloalkyloxy, alkyl, cycloalkyl, alkenyl, alkynyl group, amino, nitro, heteroaryl and aryl; Or
Naphthyl, this naphthyl can be selected from the substituting group one of following groups or repeatedly be replaced, and substituting group is selected from: halogen, CF 3, CN, alkoxyl group, cycloalkyloxy, alkyl, cycloalkyl, alkenyl, alkynyl group, amino, nitro, heteroaryl and aryl, supplementary condition are: if R is a hydrogen, R then 4Not phenyl, 3-trifluoromethyl or 4-fluorophenyl; If or R is methyl, then R 4Not phenyl, 4-bromophenyl, 4-chloro-phenyl-, 4-fluorophenyl or 4-p-methoxy-phenyl.
2. the compound in the claim 1, or its pharmaceutically acceptable addition salt, it is (±)-3-(3, the 4-dichlorophenyl)-8-methyl-8-azabicyclo (3.2.1) oct-2-ene (±)-3-(3, the 4-dichlorophenyl)-8-azabicyclo (3.2.1) oct-2-ene, (±)-8-methyl-3-(4-trifluoromethyl)-8-azabicyclo (3.2.1) oct-2-ene, (±)-3-(4-chloro-phenyl-)-8-azabicyclo (3.2.1) oct-2-ene.
3. pharmaceutical composition, this pharmaceutical composition contains the compound in the claim 1 for the treatment of effective dose, and at least a pharmaceutically acceptable carrier or thinner.
4. compound prepares the purposes of the medicine that is used for the treatment of imbalance that life animal body (comprising the mankind) is arranged or disease in the claim 1, and this imbalance or disease are with to suppress monoamine neurotransmitter re-uptake in central nervous system relevant.
5. according to the purposes of claim 4, be used for preparation and be used for the treatment of the imbalance that life animal body (comprising the mankind) is arranged or the medicine of disease, this imbalance or disease are relevant with inhibition serotonin neurotransmitter re-uptake in central nervous system.
6. according to the purposes of claim 4, be used for preparing the purposes of the medicine that is used for the treatment of depressed and related disorder, above-mentioned imbalance comprises, pseudodementia or Ganser ' s syndromes, obsessional idea and behavior disease, alarmed disease, the loss of memory, attention forfeiture superfunction disease, obesity, anxiety disorder and eating disorder.
7. the purposes of compound or its pharmaceutically acceptable addition salt among the claim 4-6, compound wherein is: (±)-3-(3, the 4-dichlorophenyl)-8-methyl-8-azabicyclo (3.2.1) oct-2-ene (±)-3-(3, the 4-dichlorophenyl)-8-azabicyclo (3.2.1) oct-2-ene, (±)-8-methyl-3-(4-trifluoromethyl)-8-azabicyclo (3.2.1) oct-2-ene, (±)-3-(4-chloro-phenyl-)-8-azabicyclo (3.2.1) oct-2-ene.
8. the method for preparing compound in the claim 1, this method comprises the dehydrating step of tool following formula: compound
Figure C9619756600041
Wherein R and R 4With the definition in the claim 1, and can at random form its pharmaceutically acceptable addition salt subsequently.
CN96197566A 1995-10-13 1996-10-11 8-azabicycle [3.2.1]oct-2-ene derivs, their preparation and use Expired - Fee Related CN1083840C (en)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
DK1156/95 1995-10-13
DK115695 1995-10-13

Publications (2)

Publication Number Publication Date
CN1199400A CN1199400A (en) 1998-11-18
CN1083840C true CN1083840C (en) 2002-05-01

Family

ID=8101642

Family Applications (1)

Application Number Title Priority Date Filing Date
CN96197566A Expired - Fee Related CN1083840C (en) 1995-10-13 1996-10-11 8-azabicycle [3.2.1]oct-2-ene derivs, their preparation and use

Country Status (24)

Country Link
US (1) US6100275A (en)
EP (1) EP0859777B1 (en)
JP (1) JP3462505B2 (en)
KR (1) KR100274829B1 (en)
CN (1) CN1083840C (en)
AT (1) ATE362931T1 (en)
AU (1) AU709327B2 (en)
BR (1) BR9610960A (en)
CA (1) CA2233541C (en)
CZ (1) CZ285093B6 (en)
DE (1) DE69637097T2 (en)
DK (1) DK0859777T3 (en)
EE (1) EE03446B1 (en)
HU (1) HUP9802433A3 (en)
IL (1) IL123583A (en)
IS (1) IS4681A (en)
NO (1) NO980919L (en)
NZ (1) NZ320216A (en)
PL (1) PL185357B1 (en)
RU (1) RU2157372C2 (en)
SK (1) SK283425B6 (en)
TR (1) TR199800628T2 (en)
UA (1) UA63894C2 (en)
WO (1) WO1997013770A1 (en)

Families Citing this family (31)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB9510459D0 (en) 1995-05-24 1995-07-19 Zeneca Ltd Bicyclic amines
AU722015B2 (en) * 1996-05-13 2000-07-20 Zeneca Limited Bicyclic amines
GB9623944D0 (en) * 1996-11-15 1997-01-08 Zeneca Ltd Bicyclic amine derivatives
GB9624114D0 (en) * 1996-11-20 1997-01-08 Zeneca Ltd Pesticidal bicyclic amine derivatives
SI20020A (en) 1996-11-26 2000-02-29 Zeneca Limited 8-azabicyclo/3.2.1/octane-, 8-azabicyclo/3.2.1/oct-6-ene-, 9-azabibyclo/3.3.1/nonane-, 9-aza-3-azabicyclo/3.3.1/nonane- and 9-aza-3-thiabicyclo/3.3.1/nonane- derivatives, their preparation and their use as insecticides
GB9624611D0 (en) * 1996-11-26 1997-01-15 Zeneca Ltd Bicyclic amine compounds
GB9706222D0 (en) * 1997-03-26 1997-05-14 Zeneca Ltd Bicyclic amine derivatives
RU2186780C2 (en) 1997-05-30 2002-08-10 Ньюросерч А/С Derivative of 8-azabicyclo[3,2,1]oct-2-ene, methods of its synthesis, pharmaceutical composition
GB9726033D0 (en) 1997-12-09 1998-02-04 Zeneca Ltd Chemical process
TWI221842B (en) * 1997-12-11 2004-10-11 Syngenta Ltd Process for the preparation of 8-azabicyclo(3.2.1)octane derivatives
ZA99681B (en) * 1998-01-28 1999-09-27 Neurosearch As 8-azabicyclo[3.2.1]oct-2-ene derivatives in labelled and unlabelled form and use of 8-azabicyclo[3.2.1]oct-2-ene derivatives in labelled or unlabelled form in diagnostic methods.
US6403605B1 (en) * 1998-05-29 2002-06-11 Queen's University At Kingston Methods for the normalization of sexual response and amelioration of long term genital tissue degradation
AU4819099A (en) * 1998-06-19 2000-01-05 Eli Lilly And Company Inhibition of serotonin reuptake
EP1133494B1 (en) * 1998-11-27 2004-02-18 Neurosearch A/S 8-azabicyclo 3.2.1]oct-2-ene and -octane derivatives
WO2000044746A1 (en) * 1999-01-28 2000-08-03 Neurosearch A/S Novel azabicyclo derivatives and their use
DE60021859T2 (en) * 1999-03-01 2006-06-01 Pfizer Inc. 1, 2, 3, 4-TETRAHYDRO-1-NAPHTHALENAMINE COMPOUNDS FOR THERAPEUTIC USE
ES2256032T3 (en) 1999-09-03 2006-07-16 Apbi Holdings, Llc USE OF DAPOXETINE, A SELECTIVE INHIBITOR OF RECOVERY OF SEROTONINE, FOR THE TREATMENT OF A SEXUAL DYSFUNCTION.
AU2049501A (en) 1999-12-20 2001-07-03 Eli Lilly And Company Benzofuran derivatives
BR0110956A (en) 2000-05-25 2003-06-10 Targacept Inc Heteroaryldiazabicycloalkanes as nicotinic cholinergic receptor ligands
US6667314B2 (en) 2000-05-26 2003-12-23 Pfizer, Inc. Tropane derivatives useful in therapy
US6579878B1 (en) 2000-07-07 2003-06-17 Targacept, Inc. Pharmaceutical compositions and methods for use
US6624167B1 (en) 2000-08-04 2003-09-23 Targacept, Inc. Pharmaceutical compositions and methods for use
DE60122015T2 (en) * 2000-10-13 2006-11-23 Neurosearch A/S TREATMENT OF AFFECTIVE DISORDERS BY COMBINED EFFECT OF A NICOTINE RECEPTOR AGONIST AND A MONOAMINERGIC SUBSTANCE
DE60231386D1 (en) 2001-04-09 2009-04-16 Neurosearch As ADENOSINE A2A RECEPTOR ANTAGONISTS IN COMBINATION WITH COMPOUNDS WITH NEUROTROPHIC ACTIVITY IN THE TREATMENT OF MORBUS PARKINSON
AR035898A1 (en) 2001-05-25 2004-07-21 Wyeth Corp ARIL-8-AZABICICLO [3.2.1] OCTANS, A PROCESS FOR THEIR PREPARATION, A FORMULATION AND THE USE OF SUCH COMPOUNDS FOR THE MANUFACTURE OF A MEDICINAL PRODUCT FOR THE TREATMENT OF DEPRESSION
WO2003094830A2 (en) * 2002-05-07 2003-11-20 Neurosearch A/S Novel azacyclic ethynyl derivatives
EP2272847A1 (en) 2005-04-08 2011-01-12 NeuroSearch A/S Enantiomers and their use as monoamine neurotransmitter re-uptake inhibitors
TW200744590A (en) * 2005-09-01 2007-12-16 Neurosearch As Novel compounds
KR100812499B1 (en) * 2006-10-16 2008-03-11 이도훈 Anticonvulsant
TWI415850B (en) * 2007-07-20 2013-11-21 Theravance Inc Process for preparing an intermediate to mu opioid receptor antagonists
AU2009221310A1 (en) * 2008-03-05 2009-09-11 Neurosearch A/S Novel 4-benzhydryl-tetrahydro-pyridine derivatives and their use as monoamine neurotransmitter re-uptake inhibitors

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0518805A1 (en) * 1991-06-13 1992-12-16 H. Lundbeck A/S Piperidine derivatives

Family Cites Families (16)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB247886A (en) * 1925-11-02 1926-02-25 Thomas Stewart Hamilton Improvements in attachments for leaf springs
US3133073A (en) * 1959-12-10 1964-05-12 Sterling Drug Inc 3-aryl-1, 5-iminocycloalkanes and preparation thereof
US3657257A (en) * 1970-08-31 1972-04-18 Robins Co Inc A H 3-aryl-8-carbamoyl nortropanes
US4180669A (en) * 1976-12-13 1979-12-25 Abbott Laboratories 2-(N-phenethyl-4-piperidino)-5-pentyl resorcinol
US4132710A (en) * 1976-12-20 1979-01-02 Ayerst, Mckenna And Harrison, Ltd. [2]Benzopyrano[3,4-c]pyridines and process therefor
FI800519A (en) * 1979-02-22 1980-08-23 Wellcome Found IMMEDIATE PREPARATIONS AND OTHER PHARMACEUTICALS OF THE EUROPEAN COMMUNITY
US5418240A (en) * 1990-08-21 1995-05-23 Novo Nordisk A/S Heterocyclic compounds and their preparation and use
DK198590D0 (en) * 1990-08-21 1990-08-21 Novo Nordisk As HETEROCYCLIC COMPOUNDS, THEIR PREPARATION AND USE
GB9019973D0 (en) * 1990-09-12 1990-10-24 Wyeth John & Brother Ltd Azabicyclic derivatives
NZ241481A (en) * 1991-02-04 1994-06-27 Hoechst Roussel Pharma Derivatives of 8-aza-bicyclo[3.2.1]octane and pharmaceutical compositions thereof
DE4200145A1 (en) * 1992-01-07 1993-07-08 Kali Chemie Pharma Gmbh 7,10-EPOXY-OXACYCLODODANE DERIVATIVES, METHODS AND INTERMEDIATE PRODUCTS FOR THEIR PREPARATION AND MEDICAMENTS CONTAINING THESE COMPOUNDS
DK154192D0 (en) * 1992-12-23 1992-12-23 Neurosearch As HETEROCYCLIC COMPOUNDS
AU672052B2 (en) * 1992-12-23 1996-09-19 Neurosearch A/S Antidepressant and antiparkinsonian compounds
CA2163095A1 (en) * 1993-05-18 1994-11-24 Huw M. L. Davies Treatment process with biologically active tropane derivatives
HU215830B (en) * 1994-04-19 2001-05-28 Neurosearch A/S Tropane-2-aldoxime derivatives pharmaceutical compositions containing them, process for producing them and their use for producing pharmaceutical compositions
US5731317A (en) * 1995-03-10 1998-03-24 Merck & Co., Inc. Bridged piperidines promote release of growth hormone

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0518805A1 (en) * 1991-06-13 1992-12-16 H. Lundbeck A/S Piperidine derivatives

Also Published As

Publication number Publication date
CZ285093B6 (en) 1999-05-12
UA63894C2 (en) 2004-02-16
JP3462505B2 (en) 2003-11-05
EP0859777A1 (en) 1998-08-26
DE69637097D1 (en) 2007-07-05
AU7291796A (en) 1997-04-30
IL123583A (en) 2003-07-31
SK283425B6 (en) 2003-07-01
PL326195A1 (en) 1998-08-31
JPH10512589A (en) 1998-12-02
ATE362931T1 (en) 2007-06-15
EE03446B1 (en) 2001-06-15
WO1997013770A1 (en) 1997-04-17
NO980919D0 (en) 1998-03-03
KR100274829B1 (en) 2000-12-15
SK28798A3 (en) 1998-09-09
DK0859777T3 (en) 2007-09-03
IL123583A0 (en) 1998-10-30
HUP9802433A2 (en) 1999-04-28
KR19990063651A (en) 1999-07-26
CN1199400A (en) 1998-11-18
CA2233541C (en) 2002-04-30
RU2157372C2 (en) 2000-10-10
IS4681A (en) 1998-03-04
NZ320216A (en) 1999-05-28
CA2233541A1 (en) 1997-04-17
PL185357B1 (en) 2003-04-30
TR199800628T2 (en) 1998-07-21
DE69637097T2 (en) 2007-09-20
EP0859777B1 (en) 2007-05-23
AU709327B2 (en) 1999-08-26
US6100275A (en) 2000-08-08
NO980919L (en) 1998-06-08
CZ75898A3 (en) 1998-11-11
EE9800062A (en) 1998-08-17
HUP9802433A3 (en) 2000-03-28
BR9610960A (en) 1999-03-02

Similar Documents

Publication Publication Date Title
CN1083840C (en) 8-azabicycle [3.2.1]oct-2-ene derivs, their preparation and use
CN1110499C (en) Spiro-quinuclidine derivatives, their preparation and use
CN1060775C (en) Fused tropane-derivatives as neurotransmitter reuptake inhibitors
CN1257499A (en) 8-Azabicyclo (3,2,1) oct-2-ene and octane derivatives as cholinergic ligands at nicotinic ACH receptors
AU690257B2 (en) Tropane-2-alcoxime derivatives as neurotransmitter reuptake inhibitors
JP2003533448A (en) Novel long-acting beta mimic, process for its preparation and its use as a medicament
CN1257500A (en) 9-azabicyclo (3,3,1) non-2-ene and nonane derivatives as cholinergic ligands at nicotinic ACH receptors
JP3841449B2 (en) Antidepressant and antiparkinsonian compounds
CN101405287B (en) Novel chromen-2-one derivatives and their use as monoamine neurotransmitter re-uptake inhibitors
CA2442423C (en) Therapeutic drug for psychoneurotic disorders
CN1124266C (en) Azacyclooctane and heptane derivatives, their preparation and usein therapy
CN1292749C (en) Novel use of 2-[5-(40fluorophenyl)3-pyridylmethylaminomethyl]
JPH06293759A (en) Alkyl-substituted heterocyclic compound
CN101563344B (en) Novel chromen-2-one derivatives and their use as monoamine neurotransmitter re-uptake inhibitors
US20040157822A1 (en) Azetidinyl diamines useful as ligands of the nociceptin receptor ORL-1
CN101812056A (en) The piperidine derivative that replaces as the novel alkyl of monoamine neurotransmitter re-uptake
US8383817B2 (en) Benztropine compounds and uses thereof
CN101072774A (en) Enantiomers of 3-heteroaryl-8h-8-azabicyclo(3.2.1)oct-2-ene and their use as monoamine neurotransmitter re-uptake inhibitors
CN1964958A (en) Novel alkyl substituted piperazine derivatives used as monoamine neurotransmitter re-uptake inhibitors
CN101563343A (en) Novel chromen-2-one derivatives and their use as monoamine neurotransmitter re-uptake inhibitors

Legal Events

Date Code Title Description
C06 Publication
PB01 Publication
C10 Entry into substantive examination
SE01 Entry into force of request for substantive examination
C14 Grant of patent or utility model
GR01 Patent grant
C17 Cessation of patent right
CF01 Termination of patent right due to non-payment of annual fee

Granted publication date: 20020501

Termination date: 20111011